Brain Atrophy

B

ProfG has been addressing the issue of brain shrinkage and asking-Which agents are the best?

We may not all agree on what is the best, but one can ask what is/are the worse.

If we can address this problem and agree, then surely it is time to say “It’s rubbish! Throw it in the Bin!” (A comment I once heard at an MS Life meeting)

The obvious answer is……yep you guessed it……

Lazy, risk-averse neurologists. who prescribe ineffective treatments

Surely we should do an Freedom of Information to find the Centres that prescribe alot of them and then one would know where to avoid:-0. These neuros are happy to prescribe treatments that are not going to do alot for most of their recipients, but they are easy to monitor.

Meanwhile tick, tock, tick, tock as your brain reserve is eaten…never to return.

Having looked at some pharma trials where their strong active drug was compared to these weak efficacy options we see people in the trials, permanently lose neurological function due to the two years on an ineffective (for the population) treatment, so pharma can get an easy positive result.

If doing trials in relapsing MS against placebo is considered unethical, Surely doing a trial against the “low-hanging fruit” is unethical too!!!

What do you think?…..The FDA (US regulators) and EMA (European regulators) surely don’t seem to care about your brain, as they seem to approve an endless stream of placebo-controlled trials

OK I sound like a stuck record and you are right and I don’t have the clinical qualifications.

Prof G is asking how do you assess brain volume loss. As this study shows you could go to a specialist imaging lab (which is why we see the same names on trial papers over and over again) or you can get a robot to measure it.

Beadnall HN, Wang C, Van Hecke W, Ribbens A, Billiet T, Barnett MH. Comparing longitudinal brain atrophy measurement techniques in a real-world multiple sclerosis clinical practice cohort: towards clinical integration? Ther Adv Neurol Disord. 2019 Jan 25;12:1756286418823462

BACKGROUND:

Whole brain atrophy (WBA) estimates in multiple sclerosis (MS) correlate more robustly with clinical disability than traditional, lesion-based metrics. We compare Structural Image Evaluation using Normalisation of Atrophy (SIENA) with the icobrain longitudinal pipeline (icobrain long), for assessment of longitudinal WBA in MS patients.

METHODS:

Magnetic resonance imaging (MRI) scan pairs [1.05 (±0.15) year separation] from 102 MS patients were acquired on the same 3T scanner. Three-dimensional (3D) T1-weighted and two-dimensional (2D)/3D fluid-attenuated inversion-recovery sequences were analysed. Percentage brain volume change (PBVC) measurements were calculated using SIENA and icobrain long. Statistical correlation, agreement and consistency between methods was evaluated; MRI brain volumetric and clinical data were compared. The proportion of the cohort with ann ualized brain volume loss (aBVL) rates ⩾ 0.4%, ⩾0.8% and ⩾0.94% were calculated. No evidence of disease activity (NEDA) 3 (no relapses, no active MRI activity or clinical progression) and NEDA 4 (NEDA 3 +brain atrophy) were also determined.

RESULTS:

Mean annualized PBVC was -0.59 (±0.65)% and -0.64 (±0.73)% as measured by icobrain long and SIENA. icobrain long and SIENA-measured annualized PBVC correlated strongly, r = 0.805 (p < 0.001), and the agreement and consistency were excellent. Weak correlations were found between MRI metrics and Expanded Disability Status Scale scores. Over half the cohort had aBVL ⩾ 0.4%, approximately a third ⩾0.8%, and aBVL was ⩾0.94% in 28.43% and 23.53% using SIENA and icobrain long, respectively. NEDA 3 was achieved in 35.29%, and NEDA 4 in 15.69% and 16.67% of the cohort, using SIENA and icobrain long to derive PBVC, respectively.

DISCUSSION:

icobrain long quantified longitudinal WBA with a strong level of statistical agreement and consistency compared to SIENA in this real-world MS population. Utility of WBA measures in individuals remains challenging, but show promise as biomarkers of neurodegeneration in MS clinical practice. Optimization of MRI analysis algorithms/techniques are needed to allow reliable use in individuals. Increased levels of automation will enable more rapid clinical translation.

We have been discussing brain atrophy and this paper looks at brain volume loss in the real world using two different methods. Whilst they pat themselves on the back on how well the two measures correlate, it means that you have lost over 0.05% more brain if you use one method over the the other. If the average low of a healthy brain is 0.2%. thats a quarter more brain:-(

SIENA although a place in Italy is actually a method for estimating brain volume. It is widely used by expert MRI reading centres to measure the percentage WBV change (PBVC) between two time points in MS studies. The proposed pathological cut off of greater or equal to ⩾0.4% annualized BVL (as measured by SIENA) has been incorporated into the criteria for ‘no evidence of disease activity’ (NEDA) four .

Icobrain long apparently a more automated solution

Whilst this is not important in the context of this post, the point I want to make is let’s look at the real-life data. In the study they looked at people on treatment

Of the 73 patients on therapy at baseline; 40 were on the CRABS. At follow up we had 96 on treatment and 38 on CRABS and 4 on alemtumab and HSCT.

Now let’s look at the Brain atrophy paper. People on treatment are loosing 0.9% per year on treatment not that great if you consider profG was extolling the virtue of effective T cell inhibition reducing brain loss down to 0.2%, which is within the normal aging range.

So go on a real life, neuro selected treatment and you lose 5 times the brain of the highly active drug….or artifically age 5 times faster. Is this acceptable?

This figure will be actually worse because half the sample had active treatments like natalizumab and fingolimod, meaning those would offset the worse treatments. Is is time to say Bye bye to CRABS

CoI: Multiple

About the author

MouseDoctor

39 comments

  • Oh mouse doctor, it really upsets me:
    “If doing trials in relapsing MS against placebo is considered unethical, Surely doing a trial against the “low-hanging fruit” is unethical too!!!”
    OF COURSE IT IS!!
    No comment…. all this crap drugs should go. And i am pretty sure neurologists should know which ones they are.

  • Great Article MD. So why did barts laud NHS when they restricted Some crab drugs on cost? I remember Prof G writing article about limiting patient choice? Surely to set example barts should ban crab drugs all together right? When we have as safe and mildly more effective drugs like tecfidera and abagio. But we both know that’s not going to happen as some of your funding comes from the same companies that make these drugs. Alas the world is grey….

    • The CRABS do work for some and people select what they want.
      In case you haven’t realised ProfG is more diplomatic than I am and he is a patient advocate and as you say based on his conflicts he does rub shoulders with pharma and they have his phone number to complain. I don’t currently have research funding from any of the CRAB makers. As for banning…remember the pwMS with MS selects what they want, and the MS nurses will also have preferences, which may influence choices too. I suspect that our prescriptions of the CRABS is not high compared to other centres (I would lovet to see the UK wide prescriptions-Pharma have the data) and just think, if I say this stuff in public just thing what I say in private.

      What gets used, changes with the times. New prescriptions.. I know the majority are not CRABS.

      • Thanks MD. Wasn’t having a go at u or Prof G. Just pointing out the obvious. Thanks for your reply. Taking Crab drugs is like taking curcumin. And yes it works very well for 50%. But then would they have done just as well without the drug? Also pharma are now doing trials using more effective drugs as placebo controls. For instance posinmod vs tecfidera.

  • Grateful for the manner of your posts MD whereby you supply the science for those who can understand it and then, as you say, put it in terms of real life.
    There’s only a small amount of the science/research I can meaningfully access, having no science or medical training and ability with maths so poor it beggars belief. But all of us can get the loss of 5x the brain of someone given higher efficacy DMTs.
    It’s makes my blood boil that every single day PwMS are losing out because of a) dinosaur neuros, b) neuros who’s hands are tied by NHS eligibility criteria and now c) the unethical brainshredding in clinical trials!

    I will add another push therefore for please tell us more about what we can do to benefit ourselves in addition to fighting for a more potent DMT, if possible. If ProfG can talk infections, exercise etc, perhaps you can shed more light on trials/studies on lipoic acid, choline, Vitamin Bs etc. Can’t imagine there aren’t a lot of us out here who haven’t already added to our supplements supply since diagnosis!

    May the CRABS become history in the near future!

    • Sorry my posts are not understandable , as for bits in the abstracts of the imaging, I have no clue what they mean either so don’t worry about that (fluid inversion recovery for example)..the physics guys think we are too stupid to try an explain in plain English and beisdes DrK doing his T1 and T2 excerises measures dont have direct pathological correlates to explain the relaxation of the protons after the magnetisatio we wouldn’t have a clue. I thing this complexitiy is a reason why the MRI

      For those new to blog CRABS are itchy things you get in your….no sorry I mean CoPaxone, rebif, avonx, and betaferon.

      The science of supplements is rather useless

        • Prof Ebers….Yes I have seen the film.

          His opinion is grounded in the world of yesteryear when CRABS were king. Now they are not and they should be spelt with a P. I have no problem with this, but survival data argues against no effect.

          However, a relevation for 2013?-I could go back to the mid 1990s for that view. As you know I have never been a fan and no it was not me involved in the original negative view back when the Risk Sharing Scheme was started. A fudge to make something available that we all knew was not very good at the population level.

      • dr md are you aware of dr Ebers ex Oxford consultant ‘s opinion?

        He seems to be aware of lack efficacy of some drugs already in 2013

        In shiftms you can sesrch by ebers or youtube ebers sclerosjs

        If you can say what is your opinion on this?

        • George Ebers was basing his opinion on the old CRAB low efficacy drugs. Things have moved on since then with the new highly effective DMTs.

      • Sorry if I wasn’t clear that I find your posts as accessible: both for the scientists and as much as they can be for someone like me – despite the science you always nail it in some straightforward manner that is eminently accessible!

        Also sorry that the supplements research is dismissible in a sentence. Guess it’s a case of continuing to consume in the hopes of some benefit.

      • A few supplements or add on therapies have indicated clear usefulness in clinical trials-

        Ibudilast: Fox, et al for the Sprint MS trial in NEJM 2018

        “Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was −0.0010 per year with ibudilast and −0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.”

        This was with <= 100 mg daily ibudilast taken over 96 weeks.

        Lipoic Acid in Neurology 2017 by Spain, et al

        "Results: Participation occurred between May 2, 2011, and August 14, 2015. Study arms of LA (n = 27) and placebo (n = 24) were matched with mean age of 58.5 (SD 5.9) years, 61% women, mean disease duration of 29.6 (SD 9.5) years, and median Expanded Disability Status Score of 6.0 (interquartile range 1.75). After 2 years, the annualized PCBV was significantly less in the LA arm compared with placebo (−0.21 [standard error of the coefficient estimate (SEE) 0.14] vs −0.65 [SEE 0.10], 95% confidence interval [CI] 0.157–0.727, p = 0.002). Improved Timed 25-Foot Walk was almost but not significantly better in the LA than in the control group (−0.535 [SEE 0.358] vs 0.137 [SEE 0.247], 95% CI −1.37 to 0.03, p = 0.06). Significantly more gastrointestinal upset and fewer falls occurred in LA patients. Unexpected renal failure (n = 1) and glomerulonephritis (n = 1) occurred in the LA cohort. Compliance, measured by pill counts, was 87%."

        This was with 1200 mg of Lipoic acid taken daily for progressive ms patients over 2 years.

        Both of these show efficacy with brain atrophy and shouldn't then be considered evidence enough for further trials as an add on therapies to existing effective DMTs like Tsyabri and Ocrevus? Considering both are really cheap?

  • ” These neuros are happy to prescribe treatments that are not going to do alot for most of their recipients”

    Of course its NOT THEIR BRAINS that are frying

  • Thanks for a clear article. One thing dear Mouse doctor – loose/lose spelling confusions. Loose = not tight “a screw loose”. Lose = to no longer have something often without intention to lose.

    • Dyslexia, can’t spell and not sure what it was written on.

      Soory there is no copy editor…there you go…..I can’t spell sorry.
      P.S. I can say it sometimes:-)….Maybe to GE 🙂

        • There are less dyslexic people in Germany I once heard. As a German speaker, I say that the spelling, compared to English, makes sense. Beautiful language. How anyone manages French, I don’t know. And I’m not dyslexic.

          • Preema! (oK I know it is Prima)
            Being a phonetic language, spelling and pronounciation of German is easier… I guess it got lost by our Angle (of Schleswig-Holstein) and Saxon (Saxony) Germanic Ancestors.
            I checked the details, the frequency can be the same dependent on based on reading ability it is similar

    • C-reactive protein is a marker inflammation and brain volume loss is associated with inflammation so there will be a correlation if you look for one/

      • BVL associated with inflammation: are you sure? Of so, how does that relate to the smoldering MS post where patients are NEDA3 yet still regressing?

        • What do you think causes brain volume loss? Current thoughts are that is inflammation…smoldering MS is inflammation. Are you asking if brain volume loss correlates with gadolium enhancing lesions as seen by MRI..I am talking biology not MRI.

          You know what i think about MRI correlations…it a sea of rather meaningless guff that does not help the individual know their MS journey.

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